Gut epithelium covers the inner layer of the gastrointestinal tract and provides a physical barrier to separate the host from its external environment, and its barrier function is critical for maintaining host health. AMP-activated protein kinase (AMPK) as a master regulator of energy metabolism plays a critical role in epithelial barrier function. AMPK activation promotes epithelial differentiation and facilitates cell polarity establishment, both of which strengthen epithelial barrier. In addition, AMPK promotes the assembly of tight junctions and adherens junctions by direct phosphorylation of proteins composing apical junctions, junctional anchors, and cytoskeletons. Pharmacological and nutraceutical compounds, as well as physiological states triggering AMPK activation strengthen epithelial barrier function. This review summarized recent progress in delineating the regulatory roles of AMPK in apical junction formation and barrier function of intestinal epithelium.
Abstract Due to the exclusive maternal transmission, oocyte mitochondrial dysfunction reduces fertility rates, affects embryonic development, and programs offspring to metabolic diseases. However, mitochondrial DNA (mtDNA) are vulnerable to mutations during oocyte maturation, leading to mitochondrial nucleotide variations (mtSNVs) within a single oocyte, referring to mtDNA heteroplasmy. Obesity (OB) accounts for more than 40% of women at the reproductive age in the USA, but little is known about impacts of OB on mtSNVs in mature oocytes. It is found that OB reduces mtDNA content and increases mtSNVs in mature oocytes, which impairs mitochondrial energetic functions and oocyte quality. In mature oocytes, OB suppresses AMPK activity, aligned with an increased binding affinity of the ATF5‐POLG protein complex to mutated mtDNA D‐loop and protein‐coding regions. Similarly, AMPK knockout increases the binding affinity of ATF5‐POLG proteins to mutated mtDNA, leading to the replication of heteroplasmic mtDNA and impairing oocyte quality. Consistently, AMPK activation blocks the detrimental impacts of OB by preventing ATF5‐POLG protein recruitment, improving oocyte maturation and mitochondrial energetics. Overall, the data uncover key features of AMPK activation in suppressing mtSNVs, and improving mitochondrial biogenesis and oocyte maturation in obese females.
<p>This file contains legends for figures supplied as supplementary data. Immunoblot evaluations of EGFR and phospho-EGFR in GIST cell lines and non-small cell lung cancer cell lines (A549 and PC-9). Actin stain is a loading control. Coordinated inhibition of IR and KIT has additive effect on cell viability in imatinib-resistant GIST430, as compared to either intervention alone, but not in imatinib-sensitive GIST882.</p>
<p>PDF file, 289KB, Western immunoblots and their densitometric analyses showing the pharmacodynamic response of GIST430 xenograft to 22 days of AT13387, imatinib or combination treatment.</p>
Abstract Background: Small airway dysfunction (SAD) is considered as a precursor of chronic airway diseases (such as COPD, asthma, etc.). As we all known, patients with COPD and asthma both exhibit infiltration of inflammatory factors in the small airways and alveoli. However, few studies have determined whether SAD is associated with airway inflammation and systemic changes in inflammatory factors. To determine whether there are changes in airway inflammation and systemic inflammatory factors in SAD population. Methods: A total of 870 subjects from Shaanxi Province, China were selected from June 2019, to April, 2021. The airway inflammation of SAD was assessed by detecting exhaled NO in the nose, air duct, small airway, and alveoli. Serum levels of inflammatory cytokines including Th1 cytokines IFN-γ and IL-2, Th2 cytokines IL-4 and IL-6, and Th17 cytokines IL-17 and TNF-α were determined by ELISA. Results: The values of FeNO 200 (small airway) of SAD, Pre-SAD and Post-SAD were all higher than those of the normal group ( P =0.012, P =0.04, P =0.037, respectively). CaNO (alveolar) of SAD, Pre-SAD and Post-SAD were all higher than those of the normal group (all P <0.0001). For Post-SAD, IL-4 is higher than normal group ( P =0.034). IL-6, IL-17 and TNF-α in SAD, Pre-SAD and Post-SAD were both higher than those in the normal group (all P <0.05). Conclusion: Patients with SAD have airway inflammation and change of systemic inflammatory factors.
Abstract Purpose: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies. Experimental Design: Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase signaling pathways. Pharmacokinetic studies were also done. Results: Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre- and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation. Conclusions: Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients. (Clin Cancer Res 2009;15(19):6258–66)
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